This application is a response to RFA MH 94-10 "Phase Two Cooperative Agreement for Genetic Studies of Bipolar Disorder and Schizophrenia." During Phase 1, known as "Diagnostic Centers for Psychiatric Linkage Studies," clinical data and DNA (including cell lines) have been collected at four centers using a common protocol. A total of 140 families with at least two bipolar I probands have been collected. The purpose of this proposal is to identify genes involved in familial bipolar disorder. The ongoing collaboration will be extended in order to genotype the families collected in Phase 1 and perform linkage analyses. In Phase 2, the four centers will continue to divide the work equally. We will employ a three stage approach to genotyping. In Stage l a genomic survey will be performed at 7 centiMorgan intervals on a panel of 524 subjects who have bipolar phenotypes or who are needed to establish phase. This panel has been selected to take maximal advantage of the affected sib-pair and affected pedigree member methods. Parametric (LOD-score) methods will also be used.The Stage II panel will include new families that were collected after Stage I. Using this more powerful sample, chromosomal regions of interest based on Stage l findings and reports from the field will be followed up. In Stage III, the sample will be expanded to include subjects' with recurrent unipolar disorder. LOD-score analyses will be performed on this sample of enlarged pedigrees with the goal of following promising findings from stages I and II. We will perform simulations of our pedigrees to determine the most powerful analytical methods of testing for linkage and heterogeneity. In addition, we will utilize the rich clinical data set in order to test various definitions of this complex phenotype. Finally, we will develop an archival database for use by the scientific community as detailed in the U O1 contracts.